Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells
Open accessAbstract
The decline of tissue regenerative potential with age correlates with impaired stem cell function. However, limited strategies are available for therapeutic modulation of stem cell function during aging. Using skeletal muscle stem cells (MuSCs) as a model system, we identify cell death by mitotic catastrophe as a cause of impaired stem cell proliferative expansion in aged animals. The mitotic cell death is caused by a deficiency in Notch activators in the microenvironment. We discover that ligand-dependent stimulation of Notch activates p53 in MuSCs via inhibition of Mdm2 expression through Hey transcription factors during normal muscle regeneration and that this pathway is impaired in aged animals. Pharmacologic activation of p53 promotes the expansion of aged MuSCs in vivo. Altogether, these findings illuminate a Notch-p53 signaling axis that plays an important role in MuSC survival during activation and is dysregulated during aging, contributing to the age-related decline in muscle regenerative potential.
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Non-cell-autonomous DNA damage response can compromise the stem cell niche and promote stem cell exhaustion.
“Also the non-cell-autonomous DDR can compromise the stem cell niche and promote stem cell exhaustion.”
From The central role of DNA damage in the ageing process (2021) · cites this paper as [86]
Old MuSCs exhibit increased cell death owing to a reduction in activity of the transcription factor p53, in a manner that is dependent on activation of the Notch pathway.
“For example, old MuSCs exhibit increased cell death owing to a reduction in activity of the transcription factor p53, in a manner that is dependent on activation of the Notch pathway95.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [95]
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References 67 · Cited by 156
- Authors
- Liu, L., Charville, G. W., Cheung, T. H., Yoo, B., Santos, P. J., Schroeder, M., & Rando, T. A.
- Affiliations
- Stanford Medicine (US)
- Hong Kong University of Science and Technology (HK)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Rando, Thomas A.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 23
- Issue
- 4
- Pages
- 544-556.e4
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC6173623
- OpenAlex
- W2889781076
- Cited by
- 156
- References
- 67
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 15 · 2023: 22 · 2022: 26 · 2021: 27 · 2020: 19 · 2019: 16
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Glenn Foundation for Medical Research
- NIH (F30 AG035521, P01 AG036695, R37 AG023806, R01 AR055755, TR01 AG047820)
- Stanford University School of Medicine
- Department of Veterans Affairs
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- Notch signaling, p53, mitotic catastrophe, skeletal muscle stem cells, aging, MDM2, muscle regeneration, stem cell proliferation, stem cell niche
- MeSH terms
- Aging, Animals, Mice, Inbred C57BL, Mitosis, Stem Cells, Signal Transduction, Tumor Suppressor Protein p53, Muscle, Skeletal, Mice, Receptors, Notch
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